The past two decades has seen the emergence of acyclic derivatives of guanine as drugs of choice for the treatment of certain viral caused conditions. The three most recognized of these acyclic derivatives are acyclovir [9-(2-hydroxyethoxymethyl)guanine], HBG [9-(4-hydroxybutyl)guanine], and ganciclovir [9-(1-hydroxymethyl-2-hydroxyethoxymethyl)guanine]. Acyclovir is the current drug of choice for the treatment of herpes simplex virus (HSV) infections; whereas, ganciclovir is the standard against which other drugs are measured for their effect against human cytomegalovirus (HCMV). The diversity of like structures which have been synthesized and evaluated for their antiviral efficacy has been the subject of recent review articles.sup.1,2. These structures are related to each other in two ways: (1) They contain some portion of the glycosyl moiety of natural nucleosides and are collectively termed acyclic nucleosides and (2) the more active compounds all contain the aglycon guanine.
A recent perspective.sup.3 reviewed the immunomodulatory properties of many 8-substituted guanosine derivatives and analogs. One of the more studied guanosine analogs with demonstrated immunomodulatory activity is 5-amino-3-(.beta.-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H, 6H)-dione (7-thia-8-oxoguanosine).sup.3-7. This nucleoside shows a broad spectrum of antiviral activity in the host animal but is virtually inactive in vitro.sup.3. Additionally, certain alkyl guanine analogs and derivatives were found to have similar activity profiles.sup.8-9. This latter work showed that neither the ribose moiety nor a portion thereof was required for immunomodulatory activity. Active guanine analogs were prepared by appending acyclic hydrocarbons of 4-6 carbon atoms in length.sup.8 to the heterocycle.
Two patents.sup.4,5 have issued which cover certain glycosyl derivatives of the thiazolo[4,5-d]pyrimidine moiety. Additionally, two journal publications.sup.6,7 describe the synthesis of glycosides of this heterocycle. Further publications.sup.10,11 have described the synthesis of aryl derivatives of thiazolo[4,5-d]pyrimidines as antimicrobials. The original syntheses of the parent heterocycles were disclosed in 1969.sup.12 and 1970.sup.13.
A number of ribonucleosides bearing a 2'-fluoro substituent in the "up" (arabino) configuration has provided a host of potent agents against several DNA viruses.sup.14-17. The best known examples are 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)thymine (FMAU) and 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-iodouracil (FIAU).
The concept of primary alkyl derivatives of guanine and guanine-like heterocycles as immunomodulators has been disclosed.sup.8,9. There are also a fair number of recent publications.sup.18-29 dealing with synthesis and biological evaluation of similar heterocyclic molecules substituted with alkenes, alkynes and allenes. However, with only one exception.sup.29 these substitutions terminate with either a phosphonate or moieties which can be phosphorylated (kinased) and thus, are designed to operate by alternate mechanisms of action when compared to the compounds of the present invention.
The present invention describes a new set of novel derivatives of thiazolo [4,5-d]pyrimidine and related heterocycles. These analogs uniquely demonstrate in vitro activity against viral infections.